Chiral Auxiliary Research Articles

Hydroxy Group-directed Diastereoselective Paternò-Büchi Reaction between Arylglyoxylates and Furfuryl Alcohols

A hydroxy group-directed Paternò-Büchi (PB) reaction between arylglyoxylates and furfuryl alcohols afforded the corresponding oxetanes regio- and diastereoselectively. Furthermore, the PB reaction between β-naphthylglyoxylate possessing diisopropyl (R,R)-tartrate moiety and furfuryl alcohol achieved high chiral induction to produce the corresponding optically pure oxetane after the removal of the chiral auxiliary.

Pd-catalyzed functionalization of alkenes and alkynes using removable tethers

The palladium-catalyzed functionalization of alkenes is a versatile transformation in synthetic chemistry, but intermolecular processes often suffer from low reactivity and selectivity. Molecular tethers can be introduced to answer these challenges. They have been used successfully for decades, but their installation and removal normally required multi-step procedures. In this review, we will present progress in this area resulting in more efficient tethering processes. We will start with a brief overview of carbamate- and sulfone-based tethered functionalization of allylic alcohol and amine derivatives. Then the recent development of tethers that can be installed in situ on (homo)-allyl/propargyl amines or alcohols for double and triple bond functionalization will be described. The difunctionalization of alkenes and alkynes using trifluoro acetaldehyde based tethers developed by our group will be covered in more details. Finally, we will introduce the concept of tethers as catalytically formed chiral auxiliaries for asymmetric synthesis.

Access to Enantiomerically Pure P-Stereogenic Primary Aminophosphine Sulfides under Reductive Conditions.

Stereochemically pure phosphines with phosphorus-heteroatom bonds and P-centered chirality are a promising class of functional building blocks for the design of chiral ligands and organocatalysts. A route to enantiomerically pure primary aminophosphine sulfides was opened through stereospecific reductive C-N bond cleavage of phosphorus(V) precursors by lithium in liquid ammonia. The chemoselectivity of the reaction as a function of reaction time, substrate pattern, and chiral auxiliary was investigated. In the presence of exclusively aliphatic groups bound to the phosphorus atom, all competing reductive side reactions are totally prevented. The absolute configurations of all P-stereogenic compounds were determined by single-crystal X-ray diffraction analysis. Their use as synthetic building blocks was demonstrated. The lithium salt of (R)-BINOL-dithiophosphoric acid proved to be a useful stereochemical probe to determine the enantiomeric purity. Insights into the coordination mode of the lithium-based chiral complex formed in solution was provided by NMR spectroscopy and DFT calculations.

Asymmetric Synthesis of Derivatives of Alanine via Michael Addition Reaction and their Biological Study

AbstractNi(II) complex of the Schiff base of the chiral auxiliary (S)-2-N-(N′-benzylprolyl)aminobenzophenone (BPB) and dehydroalanine as the initial complex in the addition reaction was investigated. The obtained four new derivatives of α-alanine were investigated as inhibitors of aldose reductase. Only one of them: (S)-2-amino-3-[(4-methylbenzyl)amino]propanoic acid showed activity. It becomes a reason for studying the patterns of biological activity of the structure of α-amino acids. The results of docking analysis indicated that (S)-2-amino-3-[(4-methylbenzyl)amino]propanoic acid demonstrated the ability to form bonds with different functional groups of the enzyme which let us assume that some amino acids of nonfunctional groups, such as Trp20 of ALR2, can play a key role in inhibitor–enzyme interactions.

A Photochemical Macrocyclization Route to Asymmetric Strained [3.2] Paracyclophanes.

The intricate frameworks of paracyclophanes are an important target for synthesis since they are found in various chiral auxiliaries, solar cells, high-performance plastics, pharmaceuticals, and molecular machines. Whereas numerous methods exist for the preparation of symmetric paracyclophanes, protocols for the efficient synthesis of strained asymmetric scaffolds are limited. Here we report a remarkably simple photochemical route to strained [3.2]paracyclophanes starting from readily available educts. By way of NMR and X-ray analyses, we discovered that UV-irradiation of an aromatic carboxylic ester tethered to a toluene moiety leads to the intramolecular formation of a new C-C bond, with loss of an alcohol. A systematic evaluation of the reaction conditions and substituents, as well as radical starter and triplet quenching experiments, point to a reaction mechanism involving an excited triplet state and hydrogen atom transfer. The new method proved to be robust and versatile enabling the synthesis of a range of cyclophanes with different substitutions, including an unusual diastereoisomer with two planar chiral centers, and thus proved to be a valuable addition to the synthetic toolbox.

Asymmetric Synthesis of Contact Sex Pheromone of Tetropium fuscum and Its Enantiomer

Tetropium fuscum is a harmful forest pest and attacks spruces. The contact sex pheromone of this pest, (S)-11-methyl-heptacosane, and its enantiomer were synthesized via Evans’ chiral auxiliaries. The key steps of this approach included acylation of carboxylic acid, diastereoselective methylation of oxazolidinone amide, and Wittig coupling of the aldehyde with chiral phosphonium salt. The synthetic pheromones would have potential utility in the control of this pest.

Ru-Catalyzed Enantioselective Hydrogenation of Diaryl 1,4-Diketones: Synthesis of Chiral 1,4-Diarylbutane-1,4-Diols.

Asymmetric hydrogenation of diaryl 1,4-diketones was achieved by using trans-RuCl2[(S)-BINAP)][(S)-Daipen] as the catalyst and the reaction gave rise to excellent enantio- and diastereoselectivities (up to >99% ee and de). This procedure provides a convenient and efficient synthetic method for chiral 1,4-diarylbutane-1,4-diols, which are important intermediates for a variety of chiral auxiliaries and ligands.

Synthesis of optically pure calix[4]arenes derived from Evans oxazolidinone and/or pyranose

Eight new optically pure calixarene derivatives, in which their lower rims were substituted with Evans oxazolidinone or pyranose moieties, are described. All macrocycles were fully characterized by NMR spectroscopy, optical rotation, and elemental analysis. The introduction of chiral auxiliaries reduced the symmetry of the macrocycle as observed by NMR. Stereospecific alkylation on the Evans oxazolidinone moiety allowed the asymmetric introduction of a methyl substituent near a phenolic position of the macrocycle.

Studies towards the Total Synthesis of Amycolamicin: A Chiral Auxiliary‐Based Diels‐Alder Approach towards the Decalin Core

AbstractThe stereoselective synthesis of (1S,2S,5R)‐5‐((4‐methoxybenzyl)oxy)‐2‐methyl‐8‐methylene‐1,2,4a,5,6,7,8,8a‐octahy‐dronaphthalene‐1‐carboxylic acid (2) is described, which comprises the bicyclic core structure of the natural product amycolamicin (1). The bicyclic ring‐system was established via an intramolecular Diels‐Alder reaction of a triene carrying a SuperQuat chiral auxiliary. The latter could be readily removed by methanolysis in excellent yield, which allowed for effective conversion of a hydroxy group at C(1) into the methylene group present in the natural product. The intramolecular Diels‐Alder reaction could also be performed with a triene incorporating a classical, phenylalanine‐derived Evans auxiliary, but the removal of the latter from the initial Diels‐Alder product was hampered by competing attack of nucleophiles on the endocyclic carbonyl group in the oxazolidinone ring. Acid 2 could be converted into an acyl cyanide that features as a key advanced intermediate in one of the three total syntheses of amycolamicin reported to date.

Controlling the Enantioselectivity in an Adaptable Ligand by Biomimetic Intramolecular Interlocking.

For the preparation of chiral drugs, both stereochemically stable and flexible catalysts in combination with chiral auxiliaries can be used. Here, chiral induction plays an important role in generating an enantiomerically pure catalyst. We demonstrate a successful approach to the spontaneous deracemization of tropos ligands for asymmetric catalysis. Three different constitutional isomers of a bisphosphinite ligand decorated with l-valine moieties (interaction units) linked to the flexible biphenyl system by a phenylene bridge for inducing a chiral switch were prepared. The substitution pattern's influence on the attached intermolecular recognition sites was systematically investigated. We can show that biomimetic intramolecular hydrogen bonding leads to a pronounced diastereoselective enrichment of one of the ligand stereoisomers. As a result, in the asymmetric Rh-catalyzed hydrogenation of prochiral olefins using these ligands, enantiomeric ratios of up to 95.8:4.2 (S) were obtained. Of particular note is the inversion of enantioselectivity relative to the previously reported BIBIPHOS-Rh catalyst due to the altered orientation of the biphenyl moiety from (Rax) to (Sax). The enantioselectivities achieved by appropriate intramolecular interlocking are remarkable for a tropos ligand/catalyst. The strategy presented here represents a powerful approach for the spontaneous alignment of tropos ligands, yielding high enantioselectivities in asymmetric catalysis.

Ultrasonic‐Assisted condensation of aromatic and aliphatic aldehydes with 3‐(Thiophen‐2‐yl)‐5‐Pyrazolone: Synthesis, characterization and Stereoselective application

AbstractA green and efficient protocol for a one‐pot condensation of 1‐(2,4‐dinitrophenyl)‐3‐(thiophen‐2‐yl)‐1H‐pyrazol‐5(4H)‐one (1) with aromatic and aliphatic aldehydes in different ratios to synthesize novel heterocyclic compounds containing pyrazolone and pyranopyrazole moieties. The reactions were conducted using the ultrasonic and traditional methods. The sonication ensured more efficiency in the rate and yield of the reactions. The structures of the synthesized compounds were elucidated by different spectroscopic methods. Additionally, an enantioselective synthesis of (R)‐ and (S)‐α‐alkylated acid was achieved using 1‐(2,4‐dinitrophenyl)‐4‐(hydroxymethyl)‐3‐(thiophen‐2‐yl)‐1H‐pyrazol‐5(4H)‐one (6) as chiral auxiliary, (S)‐4‐Methyl‐5‐nonanol the aggregation pheromone of red palm weevil was efficiently prepared and used for trapping the red palm weevil.

Selective Hydrogenation of L‐proline to L‐prolinol over Al2O3‐supported Pt‐MoOx Catalyst

AbstractL‐proline, one of abundant amino acids, can be utilized as a biobased feedstock for the synthesis of an amino alcohol, L‐prolinol, which serves as chiral auxiliary in a variety of asymmetric synthesis. Herein we examined selective hydrogenation of L‐proline into L‐prolinol over M−MoOx/Al2O3 (M=Pt, Rh, Pd, and Ru) in aqueous H3PO4 solution. Pt‐MoOx/Al2O3 exhibited high activity among the catalysts, affording L‐prolinol in 75 % selectivity and >99.9 % enantiomeric excess, while Pt/Al2O3 was inactive. Mo species were highly dispersed as a polyoxo cluster on both Pt nanoparticles and Al2O3 support, and participated concertedly with Pt nanoparticles in the hydrogenation. Activated carboxyl group of L‐proline by MoOx species on Pt nanoparticle are readily hydrogenated with dissociative hydrogen formed on the same Pt nanoparticle with MoOx species, giving an effective route for the hydrogenation of L‐proline. Pt‐MoOx/Al2O3 could be identified as an active and reusable catalyst due to no loss of its original activity.

Synthesis of Sulfur-Stereogenic Sulfoximines via Co(III)/Chiral Carboxylic Acid-Catalyzed Enantioselective C–H Amidation

Sulfoximines bearing stereogenic sulfur atoms are ubiquitous motifs in pharmaceuticals, agricultural chemicals, and bioactive compounds. Herein, we report the synthesis of sulfur-stereogenic sulfoximines via Co(III)/chiral carboxylic acid-catalyzed enantioselective C–H amidation. A broad range of cyclic and acyclic sulfur-stereogenic sulfoximines were isolated in good yields and enantioselectivities (up to an 86% yield and 1.5:98.5 er). The acyclic amidation products can be reduced to potential N,S-chiral sulfoxide ligands, which could be further transformed into recyclable chiral auxiliaries in the Pd-catalyzed diastereoselective C(sp3)–H activation of aliphatic carboxylic acids.

Silicon‐Stereogenic Monohydrosilane: Synthesis and Applications

AbstractOptically active organosilanes have been demonstrated to be versatile chiral reagents in synthetic chemistry since the early seminal contributions by Sommer and Corriu. Among these silicon‐containing chiral architectures, monohydrosilanes, which bear a Si−H bond, hold a unique position because of their facile transformations through stereospecific Si–carbon or Si–heteroatom bond‐formation reactions. In addition, those compounds have also been leveraged as chiral reagents for alcohol resolution, chiral auxiliaries, mechanistic probes, as well as potential optoelectronic materials. This Minireview comprehensively summarizes the synthesis and synthetic applications of silicon‐stereogenic monohydrosilanes, particularly the advances in the transition‐metal‐catalyzed asymmetric synthesis of this class of functional molecules.

Silicon-Stereogenic Monohydrosilane: Synthesis and Applications.

Optically active organosilanes have been demonstrated to be versatile chiral reagents in synthetic chemistry since the early seminal contributions by Sommer and Corriu. Among these silicon-containing chiral architectures, monohydrosilanes, which bear a Si-H bond, hold a unique position because of their facile transformations through stereospecific Si-carbon or Si-heteroatom bond-formation reactions. In addition, those compounds have also been leveraged as chiral reagents for alcohol resolution, chiral auxiliaries, mechanistic probes, as well as potential optoelectronic materials. This Minireview comprehensively summarizes the synthesis and synthetic applications of silicon-stereogenic monohydrosilanes, particularly the advances in the transition-metal-catalyzed asymmetric synthesis of this class of functional molecules.

Simple approach for the synthesis of a 1,1'-(ethane-1,2 diylbis(azanediyl))bis(pentan-2-ol): 13C/1H NMR spectroscopy and electrical characterizations

1,1'-(Ethane-1,2-diylbis(azanediyl))bis(pentan-2-ol) a β-aminoalcohol material denoted as 2a has been successfully synthesized. A white highly pure transparent material has been obtained after purification by chromatography techniques. Infrared spectroscopy has been used to identify the −NH and −OH functional groups. 1 H and 13 C NMR spectroscopy has confirmed the proposed structure. Complex Impedance Spectroscopy indicates an insulator behavior of the studied materials in the 313-393°C temperature range. Conductivity within this material is in intragrain contribution and its activation energy is about 1.3 eV. The physical properties of the studied material allow to consider β-amino alcohols as versatile intermediates for many organic compounds in the making of natural and synthetic originated biologically active compounds. They are widely used as β-blockers, insecticidal agents, and chiral auxiliaries.

Photocatalytic Reductive Olefin Hydrodifluoroalkylation Enabled by Tertiary Amine Reductants Compatible with Complex Systems.

Noncanonical amino acids (NCAAs) are imperative to many facets of chemistry and biology. Herein, we report a method for the reductive hydrodifluoroalkylation of olefins that utilizes triethylamine base as the terminal reductant. The alkene acceptors include a range of electronically diverse alkenes, chief among them, dehydroalanine in variously protected forms, which provides access to synthetically relevant NCAA scaffolds under mild and general reaction conditions. We have demonstrated that a chiral auxiliary may be incorporated to provide diastereocontrol for pro-stereogenic substrates. Mechanistically motivated experiments provide some insight into the reaction mechanism, which supports a terminal step involving proton transfer for electron-poor olefins, while H atom transfer assisted by a thiol cocatalyst may complete the catalytic cycle for electron-rich olefins. The protocol is found to be compatible with additions to complex molecules, including the natural product thiostrepton.

Synthesis of fluorinated pyrrolizidine, indolizidine and quinolizidine derivatives

This review provides literature data dealing with the synthesis of fluorinated pyrrolizidines, indolizidines, and quinolizidines. Synthesis of trifluoromethylated derivatives requires to use of commercially available building blocks bearing pre-installed trifluoromethyl group or synthetic trifluoromethylated templates incorporating a chiral auxiliary as starting materials. On the other hand, nucleophilic or radical difluoromethylation followed by cyclization reactions using different types of stable and readily available difluoromethylating agents was established as an efficient approach for the synthesis of difluoromethylenated pyrrolizidines, indolizidines, and quinolizidines. Furthermore, a new possibility to synthesize monofluorinated quinolizidines opens the reaction of α-trifluoromethyl alkenes and dihydroisoquinoline acetic acids using visible light photocatalysis. Generality and limitations of these methods are discussed

Highly diastereoselective asymmetric syn-aldol reactions of (R)-(N-tosyl)phenylalaninol propionate-derived titanium enolate and bidentate aromatic and aliphatic aldehydes

Asymmetric aldol reactions of ester-derived titanium enolates of (R)-(N-tosyl)phenylalaninol propionate and bidentate aromatic aldehydes has been investigated. Substrate scope of this aldol reaction was examined with a variety of bidentate aromatic aldehydes to provide syn-aldol products with high diastereoselectivity and isolated yields. Both enantiomers of N-(tosyl)phenylalaninol are readily prepared from commercially available and optically active phenylalaninol. Mild saponification removed the chiral auxiliary and furnished optically active β-hydroxy carboxylic acids.

Enantioselective hydrogen-bond-donor catalysis to access diverse stereogenic-at-P(V) compounds.

The stereoselective synthesis of molecules bearing stereogenic phosphorus(V) centers represents an enduring challenge in organic chemistry. Although stereospecific nucleophilic substitution at P(V) provides a general strategy for elaborating optically active P(V) compounds, existing methods for accessing the requisite chiral building blocks rely almost entirely on diastereocontrol using chiral auxiliaries. Catalytic, enantioselective methods for the synthesis of synthetically versatile stereogenic P(V) building blocks offer an alternative approach to stereogenic-at-P(V) targets without requiring stoichiometric quantities of chiral control elements. Here, we report an enantioselective hydrogen-bond-donor-catalyzed synthesis of aryl chlorophosphonamidates and the development of these products as versatile chiral P(V) building blocks. We demonstrate that the two leaving groups on these chlorophosphonamidates can be displaced sequentially and stereospecifically to access a wide variety of stereogenic-at-P(V) compounds featuring diverse substitution patterns.